Schwab And England Activities Of Daily Living Research Articles

Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women

Progressive supranuclear palsy (PSP) is a pure tauopathy, implicating davunetide, enhancing Tau-microtubule interaction, as an ideal drug candidate. However, pooling patient data irrespective of sex concluded no efficacy. Here, analyzing sex-dependency in a 52 week-long- PSP clinical trial (involving over 200 patients) demonstrated clear baseline differences in brain ventricular volumes, a secondary endpoint. Dramatic baseline ventricular volume-dependent/volume increase correlations were observed in 52-week-placebo-treated females (r = 0.74, P = 2.36–9), whereas davunetide-treated females (like males) revealed no such effects. Assessment of primary endpoints, by the PSP Rating Scale (PSPRS) and markedly more so by the Schwab and England Activities of Daily Living (SEADL) scale, showed significantly faster deterioration in females, starting at trial week 13 (P = 0.01, and correlating with most other endpoints by week 52). Twice daily davunetide treatments slowed female disease progression and revealed significant protection according to the SEADL scale as early as at 39 weeks (P = 0.008), as well as protection of the bulbar and limb motor domains considered by the PSPRS, including speaking and swallowing difficulties caused by brain damage, and deterioration of fine motor skills, respectably (P = 0.01), at 52 weeks. Furthermore, at 52 weeks of trial, the exploratory Geriatric Depression Scale (GDS) significantly correlated with the SEADL scale deterioration in the female placebo group and demonstrated davunetide-mediated protection of females. Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients.

Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of neurodegeneration with brain iron accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) scale, Schwab and England Activities of Daily Living (SE-ADL) scale and the Pediatric Quality of Life Inventory (PedsQL). We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9 years and the median diagnostic delay was 5 years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16 years with the disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale score showed no significant progression over time. The SE-ADL scale and the patient- and parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points, respectively. No patient subpopulations were identified based on longitudinal trajectories. Our cross-sectional results define the order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help to shorten diagnostic delay and aid in counselling patients, parents and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.

Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson's disease.

To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson's disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies. Data were obtained from Parkinson's Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson's-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort. Median follow-up was 30months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01-1.27), 3.26 (1.39-7.61), 1.87 (1.16-2.99), 5.45 (1.40-21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort. Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

Early Autonomic Symptoms Predict Functional Decline in Parkinson’s Disease Independent of Dopaminergic Therapy

Introduction: Parkinson’s disease (PD) has variable progression; identifying determinants of functional decline in PD is needed for accurate prognostication. Autonomic symptoms can result from dopaminergic therapy but may also independently predict functional decline. Methods: The sample included individuals with newly diagnosed PD in Parkinson’s Progression Markers Initiative. Autonomic symptoms were measured with the Scales-for-Outcomes-in-Parkinson’s-Disease-Autonomic (SCOPA-AUT). Presence/absence of autonomic symptoms for SCOPA-AUT total scale and seven subscales was defined, and baseline demographic/clinical data were compared between groups with and without autonomic symptoms. Time-to-functional-dependence, or Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤70, was compared between groups using hazard models, adjusting for covariates including time-varying levodopa-equivalent daily dosage. If a subscale was associated with a significant subhazard ratio (SHR), hazard models for items in that subscale were generated and gender was evaluated as an effect modifier. Results: 399 participants were included. Over a median of 72 months (range 6–84), 91 (22.81%) reached SE-ADL ≤70. SCOPA-AUT total/gastrointestinal/urinary/pupillomotor scales were associated with SE-ADL ≤70; respective multivariable SHRs (95% CI, p value) were 1.98 (1.06–3.70, 0.03), 1.71 (1.04–2.81, 0.03), 1.94 (1.25–3.01, <0.01), 2.56 (1.24–5.31, 0.01). Individual items in the gastrointestinal and urinary scales drove associations. Urinary scale associations were seen in males only. Conclusions: Symptoms of gastrointestinal, urinary, pupillomotor dysfunction are associated with functional decline risk in PD, independent of dopaminergic therapy. Detailed assessments of autonomic symptomatology should be utilized in studies attempting to refine predictive models of PD progression.

Associations Between Amantadine Usage, Gait, and Cognition in PSP: A post-hoc Analysis of the Davunetide Trial.

Introduction: Amantadine anecdotally improves gait in progressive supranuclear palsy (PSP) but definitive data is lacking. We investigated associations between amantadine usage, gait, cognition, and activities of daily living in 310 subjects with PSP using data from the davunetide trial.Method: We compared baseline demographics, PSP Rating Scale (PSPRS), Repeat Battery for the Assessment of Neuropsychological Status (RBANS), and Schwab and England Activities of Daily Living (SEADL) scores between subjects taking vs. not taking amantadine using chi-square tests for categorical variables and independent sample t-tests for continuous variables. Using the general linear model (GLM), we tested whether group status predicted total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, and SEADL before and after the 52-weeks follow-up.Results: Subjects taking vs. not taking amantadine were similar at baseline, except subjects taking amantadine had a higher Clinical Global Impression (CGI) Score (p = 0.01). However, the CGI change score did not differ between groups at week 52 (p = 0.10). Using GLM models (controlling for covariates), we found that subjects taking vs. not taking amantadine did not significantly predict total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, or SEADL at baseline, week 52, or the change score between baseline and week 52.Discussion: This post-hoc analysis of the davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes.

Application of intracranial lead reconstruction in deep brain stimulation therapy in patients with Parkinson's disease

To evaluate the feasibility of applying intracranial lead reconstruction in deep brain stimulation (DBS) therapy for Parkinsonism. We retrospectively collected the clinical data from 27 patients with Parkinson's disease (PD), who received bilateral subthalamic nucleus (STN) DBS therapy between January, 2016 and December, 2017. According to the position of the selected optimal stimulating contact of the implanted leads, the patients were divided into group A with the stimulating contacts of the bilateral leads in the STN, group B with unilateral stimulating contacts in the STN, and group C with bilateral stimulating contacts outside the STN. All the patients were assessed for improvement using Hoehn-Yahr stage, the third part of United Parkinson's Disease Rating Scale (UPDRS Ⅲ), Schwab and England Activities of Daily Living (SE-ADL), and L-dopa equivalent daily dose (LEDD). The consistency between the optimal stimulating contact selected by lead reconstruction and that by standard postoperative programming procedure was also evaluated. The patients in all the 3 groups showed postoperative improvements in Hoehn-Yahr stage, UPDRS Ⅲ score, SE-ADL score, and LEDD in the medication-off state. But at 12 months of the follow-up, such improvements were maintained only in the patients of group A. The optimal stimulating contacts selected by lead reconstruction and standard postoperative programming procedure had a matching rate of up to 77.78% (42/54), and the coordinates of the optimal contacts selected by the two methods showed no significant difference. Intracranial lead reconstruction facilitates the study of the association between the implant site of the leads and the clinical outcome of DBS therapy for PD and allows the precise selection of the optimal contact of the implanted leads in postoperative programming of DBS.

Vastly Different Exercise Programs Similarly Improve Parkinsonian Symptoms: A Randomized Clinical Trial

Objectives: To directly compare the effects of agility exergaming (EXE) and stationary cycling (CYC) exercise training on Parkinson’s disease (PD) patients’ mobility and clinical symptoms. Design: Randomized clinical trial. Setting: Outpatient physiotherapy clinic in a hospital. Participants: Seventy-four stage 2–3, nondemented PD patients were included in this study. Intervention: The groups were as follows: EXE (n = 25), CYC (n = 25), and a wait-listed control group (CON; n = 24). The EXE and CYC groups exercised 5×/week for 5 weeks, matched at 80% of the age-predicted maximal heart rate. Main Outcomes: The primary outcome was the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (UPDRS-II) score. Secondary outcomes were Parkinson’s Disease Quastionnaire-39 (PDQ-39), the Beck Depression Inventory (BDI), the Schwab and England Activities of Daily Living (SE-ADL) scale, Euro-Quality of Life-5 Dimensions (EQ-5D) questionnaire, the Berg Balance Scale (BBS), the Balance Evaluation Systems Test (BESTest), the Tinetti Assessment Tool (TAT), the Dynamic Gait Index, the 6-min walk test (6MWT), and standing posturography. Results: After treatment, UPDRS-II scores improved (mean change: EXE, –4.5 points; CYC, –3.2 points). The results for the other outcomes (EXE and CYC, respectively) were: PDQ, 13 and 17%; BDI, –2.5 and –2.1 points; 6MWT, 129.6 and 141.6 m; and EQ-5D, 12 and 9% (all p < 0.05, but there was no difference between groups). EXE vs. CYC resulted in improved SE-ADL (8.4 and 4.0 points, effect size [ES]: 0.12), BBS (8.8 and 4.2 points, ES: 0.44), and 2 measures of posturography (ES: 0.11 and 0.21) (p < 0.05). BESTtest, TAT, the Dynamic Gait Index, and 4 out of 6 posturography measures did not change (p > 0.05). Conclusion: Two highly different exercise programs resulted in similar improvement of most motor and clinical symptoms in PD patients.

PND124 - HUMANISTIC AND ECONOMIC BURDEN OF PROGRESSIVE SUPRANUCLEAR PALSY: A SYSTEMATIC LITERATURE REVIEW

Progressive supranuclear palsy (PSP) is a rare neurological disease that is characterized by a primary tau pathology. PSP symptoms include early and severe gait instability with falls, slowing of vertical saccadic eye movements, slowed movement, rigidity of the axial musculature, dysphagia, dysarthria, pseudobulbar affect, neuropsychiatric abnormalities, and dementia. There are currently no available treatments for patients with PSP. The objective of this research was to review the available evidence on humanistic and economic burden of PSP, as a foundation work for understanding the unmet needs of this population. A systematic literature review was conducted in 9 databases including Medline and Embase in 2000-2017, supplemented with hand searches of reference lists. Where available, PSP Richardson syndrome (PSP-RS) and other phenotypes were assessed. Health utility (as reported by EQ5D) was measured in 5 studies with a mean utility ranging 0.20-0.41 after mean disease duration of 4.7-6.1 years. PSP patients had the most difficulties with usual activities followed by mobility and self-care. Four studies investigated the gradual worsening of daily activities in the Schwab and England Activities of Daily Living (SEADL) scale and described fast disease progression (annual worsening exceeded 10 points on the 100-point scale). Annual worsening in Clinical Global Impression (CGI) was in the 0.7-0.9 range. Healthcare resource utilization was reported in 5 studies, describing wheelchair dependence, urinary catheterization, tube feeding, hospitalizations, and residential care as important cost drivers. PSP patients typically receive informal care from family members who experienced high psychological strains. Most PSP studies report severely diminished quality of life with rapidly worsening functions. Humanistic and economic burden by PSP disease states or progression levels should be further investigated, to allow subsequent development of health economic models for the value assessment of emerging treatments promising slower PSP progression.

Cathepsin S increases tau oligomer formation through limited cleavage, but only IL-6, not cathespin S serum levels correlate with disease severity in the neurodegenerative tauopathy progressive supranuclear palsy.

Limited cleavage promotes the aggregation propensity of protein tau in neurodegenerative tauopathies. Cathepsin S (CatS) is overexpressed in brains of patients suffering from tauopathies such as Alzheimer's disease (AD). Furthermore, CatS serum levels correlate with survival in the elderly. The current study investigates whether limited cleavage by CatS promotes tau aggregation, and whether CatS serum levels may correlate with disease severity in tauopathies. Oligomer formation of fluorescently labeled protein tau was monitored by single particle fluorescence spectroscopy after coincubation with CatS. Tau cleavage patterns were investigated by SDS-PAGE. For serum analyses, samples were collected from 42 patients with probable progressive supranuclear palsy (PSP) according to NINDS-PSP criteria. Disease severity was assessed by PSP rating scale (PSP-RS), PSP staging system (PSP-S) and Schwab and England Activities of Daily Living (SEADL). CatS, cystatin C (CysC) and interleukin 6 (IL-6) serum levels were determined by ELISA, ECLIA and turbidimetry, respectively. SDS-PAGE demonstrated a distinct cleavage pattern of protein tau after coincubation with CatS. Furthermore, tau oligomer formation was increased 2.4-fold (p<0.05) after limited cleavage. Serum CatS and CysC levels did not correlate with disease severity in PSP. Of note, IL-6 correlated with PSP-S (r=0.41; 95% CI 0.11-0.65; p=0.008), SEADL (r=-0.37; 95% CI -0.61 to -0.06; p=0.017) and the history and gait/midline subdomains of the PSP-RS. While CatS facilitates tau aggregation in vitro, serum levels of CatS appear not to correlate with disease severity. The observed correlation of IL-6 with disease severity warrants further investigation of inflammatory markers in PSP.

PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy.

To date, pharmacological treatment options for progressive supranuclear palsy (PSP), a neurodegenerative tauopathy, are limited. The MAO-B inhibitor rasagiline has shown neuroprotective effects in preclinical models of neurodegeneration. To evaluate the safety, tolerability and therapeutic effect of rasagiline on symptom progression in PSP. In this 1-year randomized, double-blind, placebo-controlled trial, 44 patients fulfilling the NINDS-PSP criteria were randomized to 1mg/d rasagiline or placebo. The combined primary endpoint included symptom progression as measured by the PSP rating scale (PSP-RS) and the requirement of L-dopa rescue medication. Secondary endpoints included Schwab and England Activities of Daily Living (SEADL), Montgomery-Åsberg Depression Rating Scale, Mini Mental State Examination, Frontal Assessment Battery and posturographic measurements. Of the 44 patients randomized, 26 completed the trial per protocol. Rasagiline was well tolerated, with a slight increase of known side effects (hallucinations, ventricular extrasystoles). No effect on the primary endpoint (p=0.496) was detected. Symptom progression averaged at 11.2 (rasagiline) and 10.8 (placebo) points per year (ΔPSP-RS). No difference was seen in SEADL, depression, cognitive function, frontal executive function and posturographic measurements. Post hoc analyses of PSP-RS subdomains indicate a potential beneficial effect in the "limb motor" subdomain, whereas performance appeared lower in the "mentation" and "history" subdomains in the treatment group. While rasagiline is well tolerated in PSP, a beneficial effect on overall symptom progression was not detected. Post hoc analyses suggest the implementation of more specific endpoints in future studies.

Clinical correlates of longitudinal brain atrophy in progressive supranuclear palsy

IntroductionThere are no effective treatments for progressive supranuclear palsy (PSP). Volumetric MRI (vMRI) may be a useful surrogate outcome measure in PSP clinical trials. The goal of the study was to evaluate the potential of vMRI to correlate with clinical outcomes from an international clinical trial population. MethodsPSP patients (n = 198) from the AL-108-231 trial who had high quality vMRI and Progressive Supranuclear Palsy Rating Scale (PSPRS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Schwab and England Activities of Daily Living (SEADL), Color Trails Test, Geriatric Depression Screen (GDS) and one year Clinician Global Impression of Change (CGIC) data from the baseline and 52 week visits were included. Linear regression was used to relate baseline values and annual clinical rating scale changes to annual regional vMRI changes (whole brain, ventricular, midbrain and superior cerebellar peduncle volumes). ResultsEffect sizes (Cohen's d) measuring disease progression over one year were largest for vMRI (midbrain [1.27] and ventricular volume [1.31]) but similar to PSPRS (1.26). After multiple comparison adjustment, annual changes in PSPRS, RBANS, SEADL, Color Trails Test, GDS and one year CGIC were modestly correlated with annual vMRI changes (p < 0.05). Baseline neuropsychological status on RBANS (p = 0.019) and Color Trails (p < 0.01) predicted annual midbrain atrophy rates. ConclusionStandard vMRI measurements are sensitive to disease progression in large, multicenter PSP clinical trials, but are not well correlated with clinical changes. vMRI changes may be useful as supportive endpoints in PSP trials.

Nonmotor Features in Parkinson's Disease: What Are the Most Important Associated Factors?

Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson's disease (PD). Methods. 268 PD patients were assessed using the validated Movement Disorders Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE). Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications. Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as “mild” or less, we found a significant cumulative effect of nonmotor symptoms on patients' mood, daily activities, and quality of life.

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial

In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Allon Therapeutics.

Different effectiveness of subthalamic deep brain stimulation in Parkinson's disease: A comparative cohort study at 1 year and 5 years

Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to produce long-term symptom improvement in Parkinson's disease. The aim of this study was to identify the target symptoms that show the most improvement at 1 year and at 5 years after STN-DBS. This was a 5-year cohort study of 41 consecutive patients treated with bilateral STN-DBS. Clinical evaluations were performed 1 month prior to surgery and 1 year and 5 years after surgery. The outcome measurements at 1 year and 5 years were the changes compared with the baseline in Unified Parkinson's Disease Rating Scale (UPDRS) parts I, II, III, and IV scores, the Hoehn and Yahr stage, and Schwab and England Activities of Daily Living (SEADL) scores in the conditions of off-medication/on-stimulation and off-medication/off-stimulation. Further analysis included changes in the levodopa equivalent daily dose. When compared to the preoperative baseline off-medication condition, significant improvements were observed in the UPDRS parts I, II, III, and IV and SEADL (p<0.001) scores in the off-medication/on-stimulation condition 1 year after STN-DBS. Five years after STN-DBS, improvements in UPDRS scores were observed only for parts II, III, and IV (p<0.001). In the off-medication/off-stimulation condition, no significant improvement was observed. At 5 years, significant deteriorations were observed in scores for the UPDRS part III axial subitem (p=0.005), UPDRS part I (p=0.005), UPDRS part II (p<0.001), and SEADL (p=0.001). The long-term effect of STN-DBS on motor function is promising, although the magnitude of its effectiveness varied over the 5-year period.

A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson's disease

Background: To the extent that excitotoxicity may play a role in the pathogenesis of certain neurodegenerative disorders, antagonists of glutamate, an excitatory neurotransmitter, should exert neuroprotective effects in these disorders, including Parkinson's disease (PD). Methods: Patients in early stages of PD, not previously treated with levodopa, were randomized to receive riluzole 50 mg capsules orally, taken twice daily or a matching placebo. All subjects were evaluated at baseline (pre-treatment), at 1, 3 and 6 months (post-treatment), and following a 6-week washout. After the washout, all subjects were offered an enrollment in an open label, 1-year, extension study. The principal investigator (JJ), however, remained blinded to the original assignment during the entire study. The patients were assessed by the Unified Parkinson's Disease Rating Scale (UPDRS), Activities of Daily Living (ADL), Hoehn & Yahr (HY) stage, and Schwab and England (SE) ADL scale. The quantitative assessments included Movement Time (MT) and Reaction Time (RT). Additionally, the time to initiate dopaminergic therapy was assessed. Safety was determined at each visit by clinical history and examination, a panel of blood safety laboratory tests including complete blood count, chemistry profile, and liver function studies. Results: Twenty patients with a mean age of 62±9.02 (range: 46–73) years and mean duration of symptoms of 18±9.53 (range: 6–36) months were enrolled. One patient withdrew from the study because he needed more aggressive treatment of his symptoms. Analysis of the efficacy variables showed no meaningful symptomatic effect of riluzole on UPDRS score. Likewise, there was no significant change in the median HY stage, SE ADL rating, or the MT/RT. Seventeen patients (mean age 62±9.26) elected to continue in the open label extension study. Although the observed deterioration in UPDRS scores seemed to be more pronounced in the placebo group than in the riluzole group, the difference did not reach statistical significance. There was no statistically significant difference in the latency between enrollment and start of symptomatic therapy when patients initially treated with riluzole were compared to those initially treated with placebo (8.3 vs 9 months). Conclusions: This pilot and extension study showed that riluzole, 100 mg/day, was well tolerated in patients with early PD. No evidence of symptomatic effect of riluzole was observed. Because of the exploratory nature of the design and small size of the study, it was not possible to determine whether riluzole affected the natural history of PD. The encouraging results from our study, however, suggest that larger, longitudinal studies are warranted.